This invention relates to topical formulations for transdermal delivery of niacin and esters and alcoholic fatty-acid esters as described herein derivatives thereof and the transdermal treatment of hyperlipidemia and hypercholesterolemia with these agents. Therapeutic uses of the system are also described. The topical formulations are useful for, e.g., treating hyperlipidemia in a mammal.
Hyperlipidemia and hypercholesterolemia are conditions that have a well established correlation with increased risk of other conditions, such as heart attacks, atherosclerosis, and other deleterious ailments. There are numerous agents available for lowering cholesterol and lipid levels, including gemfibrizol, probucol, and, more recently, the xe2x80x9cstatinsxe2x80x9d e.g, lovastatin.
Niacin (nicotinic acid), a water soluble B-complex vitamin, is used orally for the treatment of hyperlipidemia and has been shown to be effective in reducing total plasma cholesterol (C), low density lipoproteins LDL-C and very low density lipoprotein triglycerides (VLDL-triglycerides), all of which are associated with health risks, while raising serum levels of high density lipoproteins (HDL-C) which are considered a xe2x80x9chealthyxe2x80x9d lipoprotein, in patients with type II, III, IV, and V hyperlipoproteinemia.
Although the mechanism by which niacin alters lipid profiles has not been well defined, its mechanisms of action have been shown to include inhibition of free fatty acid release from adipose tissue (see Carlson, L. A., Froberg, S. O. and Nye, E. R., Nicotinic acid in the rat. 11. Acute effects of nicotinic acid on plasma, liver, heart, and muscle lipids, Acta Med Scand 180: 571-579, 1966), and increased lipoprotein lipase activity (see Priego, J. G., Pina, M., Armijo, M., Sunkel, C. and Maroto, M. L., Action of etofibrate, clofibrate and nicotinic acid on the metabolism of lipids in normolipemic rats. Short term effects and method of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than 14 million Americans have elevated blood LDL-C levels. HMG-CoA reductase inhibitors (statins) are the most widely used class of drugs for treating patients with elevated levels of LDL-C. Niacin, however, is the only drug recommended by the American Heart Association for HDL improvement in primary prevention of cardiovascular diseases in addition to lowering LDL-C. Niacin therapy is not only very cost-effective as a monotherapy but it also is beneficial as a combination therapy because it complements the effects of other classes of lipid-lowering drugs. Niacin is a second or third choice for isolated, hypercholesterolemia because of a high incidence of side effects associated with oral niacin therapy. However, it has a therapeutic advantage as a monotherapy when reduction of both LDL-C and triglycerides are desired such as for patients with severe combined hyperlipidemia. Niacin can also be used in combination with other cholesterol-lowering agents such as the xe2x80x9cstatinsxe2x80x9d to maximize lipid-lowering activity. One study shows that a niacin/lovastatin combination is highly effective in lowering LDL-C, triglycerides and lipoprotein a[Lp(a)] while retaining niacin""s potency in raising HDL-C (Kashyap, M. L., Evans R., Simmons, P. D., Kohler, R. M. and McGoven, M. E., New combination niacin/statin formulation shows pronounced effects on major lipoproteins and well tolerated, J Am Coll Card Suppl. A 35: 326, 2000).
Niacin has been widely used for reducing serum cholesterol levels because it is considered a cost-effective therapy. In oral doses of 2 to 3 g daily, it reduces levels of total and LDL-C by an average of 20% to 30%, reduces triglyceride levels 35% to 55%, increases HDL-C 20% to 35%, and reduces Lp(a) in humans. Niacin also reduces total mortality as well as mortality from coronary artery disease (see The Coronary Drug Project Research Group, JAMA 231: 360-381, 1975; and Canner, P. L., Berge, K. G., Wenger, N. K., Stamler, J., Friedman, L., Prineas, R. J. and Friedewald, W., Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin, J Am Coll Cardiol 8: 1245-1255, 1986.) and it helps to slow or reverse the progression of atherosclerosis (see Blankenhorn, D. H., Nessim, S. A., Johnson, R. L., Samnarco, M. E., Azen, S. P. and Cashin-Hemphill, L., Beneficial effects of combined colestipol-niacin therapy on coronary atheroscloerosis and coronary venous bypass grafts, JAMA 257: 3233xe2x80x943240, 1987.; and Cashin-Hemphill L.; Mack, W. J., Pogoda, J. M., Samnarco, M. E., Azen, S. P. and Blankenhorn, D. H., Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up, JAMA 264: 3013-3017, 1990).
Oral niacin therapy has side effects that limit its utility. Although niacin is a vitamin, it must be used in therapeutic doses to lower cholesterol. At these doses, both immediate-release and sustained-release niacin can have several side effects. The most common side effect of niacin is flushing, a warm feeling in the skin usually associated with redness and sometimes itching. Flushing is not dangerous but most patients find it very uncomfortable, which seriously limits patient compliance with therapy. Niacin-induced flushing can be substantially attenuated by pretreatment with cyclooxygenase inhibitors, suggesting that the vasodilation is caused by a prostaglandin-mediated mechanism (see Carlson, L. A., Nicotinic acid and inhibition of fat mobilizing lipolysis. Present status, of effects on lipid metabolism, Adv Exp Med Biol 109: 225-23 8, 1978).
Liver function tests are always monitored in patients taking niacin since elevation of serum transaminase levels has been associated with niacin treatment, and sustained-release niacin formulations have been associated with more serious liver problems (see McKenney, J. M., Proctor, J. D., Harris, S., and Chinchili, V. M., A comparison of the efficacy and toxic effects of sustained- vs immediate-release niacin in hypercholesterolemic patients, JAMA 271: 672-777, 1994; and Stafford, R. S., Blumenthal, D. and Pasternak, R. C., Variations in cholesterol management practices of U.S. physicians, J Am Coll Cardiol 29: 139-146, 1997). Other possible side effects of oral niacin therapy include activation of peptic ulcers, gout, and worsening of diabetes control. Given the potential for side effects, oral niacin therapy requires careful clinical monitoring.
The pharmacokinetic profile of niacin taken orally is complex due to rapid and extensive first-pass metabolism, resulting in a nonlinear relationship between niacin dose, thus there is no correlation between the lipid parameters and plasma niacin levels. For example, data show that Niaspan(copyright) doses of 1,000 mg results in an improvement in lipid profiles with barely detectable increases in plasma niacin (see Physicians Desk Reference, 53rd edition, p 1505-1506, 1999). Niaspan(copyright) is an extended release niacin formulation approved by the FDA for the treatment of hypercholesterolemia and hypertriglyceridemia (Capuzzi, D. M., Guyton, J. R., Morgan, J. M., Goldberg, A. C., Kriesberg, R. A., Brusco, O. A. and Brody, J., Efficacy and safety of an extended-release niacin (Niaspan): A long term study, Am J Cardiol 82: 74u-8 I u, 1998; and Morgan, J. M., Capuzzi, D. M., and Guyton, J. R., A new extended-release niacin (Niaspan): Efficacy, tolerability, and safety in hypercholesterolemic patients, Am J Cardiol 82: 29u-34u, 1998). Thus, significant improvement in the serum lipid profile can be achieved without a dramatic increase in nicotinic acid plasma levels after the oral administration of niacin (see Knopp, R. H., Alagona, P., Davidson, M., Goldberg, A. C., Kafonek, S. D., Kashyap, M., Sprecher, D., Superko, H. R., Jenkins, S., Marcovina, S., Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia, Metabolism 47: 1097-104, 1998). This demonstrates that sustained elevation of blood levels of niacin is not required to achieve a therapeutic effect. Indeed, the data support the argument that tissue saturation with niacin appears to be the key factor in obtaining therapeutic benefit. Prolonged low-level exposure via controlled release oral formulations is preferable to the high level, short exposures resulting from immediate release formulations because it avoids inconvenient dosing regimens and reduces unpleasant side effects. However, controlled release oral formulations of niacin still show significant degree of flushing and hepatic dysfunction. In view of the pharmacokinetic fate of oral niacin, the ideal method of niacin administration has yet to be achieved.
Transdermal drug delivery is an attractive route due to the controlled input of these agents and avoidance of the hepatic first-pass effect. However, it is unlikely that hydrophilic compounds such as niacin will easily permeate across the skin. We demonstrate in the present study that the chemical modification with fatty alcohols allows niacin to permeate the skin in a controlled manner for systemic delivery and to affect the blood lipid profile in animal models. Both chemical and enzymatic hydrolysis of prodrug esters of niacin have been extensively evaluated using human and rat plasma and hog liver carboxylesterase preparations described by Wernly-Chung, G. N., Mayer, J. M., Tsantili-Koulidou, A. and Testa, B., Structure-reactivity relationships in the chemical hydrolysis of prodrug esters of nicotinic acid, Int J Pharma 63: 129-134, 1990. The studies show that chemically stable niacin esters are excellent substrates of esterases. A study indicates that the binding of niacin esters mainly depends on lipophilicity (optimal log Poct/w=2.3) and steric factors. Niacin esters up to hexyl nicotinate are commercially available.
Transdermal delivery systems are a convenient and effective alternative for the administration of many types of medications, including anti-anginals (nitroglycerin), hormones (estrogens) and antihypertensives (cloncidine). Transdermal delivery is beneficial because the agents are delivered directly into the blood stream, avoiding first-pass metabolism in the liver, so that drug delivery is continuous and sustained. Transdermal delivery also provides a sustained and consistent delivery of medication, avoiding peaks and valleys in blood levels which are often associated with oral dosage forms and which are usually undesirable. Thus, using transdermal delivery, one can administer lower doses of drug to achieve the same therapeutic effect compared to oral administration, reducing or eliminating dose-dependent side effects.
Preparing suitable formulations of medications is a challenging task, and many hurdles must be overcome to achieve a suitable topical dosage form. The skin, which has protective layers designed to prevent penetration of foreign matter, must be sufficiently penetrated to provide the active agent to the desired site for absorption into the bloodstream. Skin is a complex organ system, consisting of multiple layers. The uppermost, or xe2x80x9cstratum corneumxe2x80x9d layer of skin consists of non-living material derived primarily from the terminal differentiation of epidermal keratinocytes, and provides a protective barrier for the underlying components of skin. The epidermis contains a number of cell types, although keratinocytes are the major cell type. Dermal fibroblasts are embedded within a matrix comprised of collagen, elastin, proteoglycans, and other extracellular matrix molecules. Blood capillaries are found in the dermis, but the epidermis is non-vascular.
Additionally, the drug itself must be suitable for administration. The size of a drug molecule, its charge, and polarity are factors that contribute to the ability of the agent to penetrate the skin to the desired site or to blood vessels for systemic distribution.
The benefits of transdermal delivery indicate that transdermal delivery systems of niacin for, e.g, the treatment of hyperlipidemia or vitamin therapy are desirable.
It is an object of the present invention to provide transdermal delivery formulations and systems for the systemic delivery of niacin to a patient, e.g., a mammal such as a human, wherein the niacin is provided in a pro-drug of niacin, e.g., nicotinic acid esters and fatty acid esters of the corresponding alcohol. These are referred to herein as xe2x80x9cpro-niacinxe2x80x9d.
It is also an object of the invention to treat hyperlipidemia and hpercholesterolemia via transdermal delivery of niacin using pro-niacin esters.
These and other objects of the invention are achieved by the present invention which is described in the following disclosure.